The authors sought to demonstrate the advantages of a selective, potent, short-acting A adenosine receptor agonist, CVT-3146 (2-(N-pyrazolyl)Ado derivative), for potential clinical use as a coronary vasodilator during myocardial perfusion imaging. The use of adenosine in a pharmacological stress test during myocardial imaging is limited by side effects mediated by A1 and A2B adenosine receptors and by its ultrashort duration of action. CVT-3146 (0.1-5 microg/kg) and adenosine (13-267 microg/kg) were given as peripheral intravenous injections in 10 awake dogs instrumented for measurement of coronary blood flow (CBF). CVT-3146 caused a dose-dependent increase of CBF (ED50 = 0.34 +/- 0.08 microg/kg, maximal increase = 221 +/- 18%, n = 6). Adenosine was less potent (ED = 51 +/- 15 microg/kg, p < 0.05) but equieffective (maximal increase in CBF = 227 +/- 11%). The increase in CBF caused by 2.5 microg/kg CVT-3146 reached 84 +/- 5% of the maximal reactive hyperemia following 20 s of coronary occlusion (n = 4). After a 10-s injection of CVT-3146 (2.5 microg/kg), the increase in CBF remained at least twofold above baseline for 97 +/- 14 s, whereas for adenosine (267 microg/kg), the twofold increase in CBF lasted only 24 +/- 2 s (p < 0.01, n = 6). A 30-s injection of 2.5 microg/kg CVT-3146 prolonged the twofold increase in CBF up to 221 +/- 20 s. No atrioventricular block was noted. At 2.5 microg/kg, the peak effect of CVT-3146 on CBF was associated with a short-lasting (20 +/- 6 s) increase in heart rate (78 +/- 9 bpm) and decrease in mean arterial blood pressure (13 +/- 6 mm Hg, p < 0.05, n = 6). CVT-3146 is a potent coronary vasodilator. Its short duration of action, minimal and transient systemic hemodynamic effects, and ease of administration may make this agonist suitable for pharmacological coronary vasodilation during myocardial perfusion imaging for noninvasive detection of subcritical arterial stenosis.

Adenosine and related compounds can produce atrioventricular (A-V) conduction block. Similar conduction disturbances are observed in myocardial hypoxia. To investigate the possibility that adenosine might be causally involved in hypoxic conduction disturbances, we measured A-V conduction times, subdivided into atrial-to-His bundle (A-H) and His bundle-to-ventricular (H-V) intervals, with extracellular electrodes in isolated rabbit and guinea pig hearts perfused with modified Krebs-Henseleit solution. Adenosine produced dose-dependent prolongation of A-V conduction time in both species, although guinea pig hearts responded to lower doses (10(-7) M) and showed a steeper dose-response relationship than rabbit hearts. Higher adenosine doses produced second-degree heart block in both species. Conduction delay was confined to the A-H interval, implicating action on A-V node cells. Further investigation of guinea pig hearts revealed a specific antagonism towards adenosine's effects by 10(-5) M aminophylline. Conduction disturbances produced by acetylcholine or MnCl2 were unaffected by aminophylline as were adenosine's effects by atropine. Perfusion with hypoxic perfusate caused A-V conduction delays and second-degree block in guinea pigs hearts. This effect was dramatically attenuated by aminophylline. We conclude that endogenously released adenosine may cause at least some of the A-V conduction disturbances associated with acute myocardial hypoxia. Furthermore, methylxanthines may prove to be of therapeutic value in combatting such disturbances in a clinical setting.

The purpose of this study was to determine the magnitude of vasodilation by CVT-3146 in different vascular beds and to compare it with that by adenosine in conscious dogs. Intravenous bolus injections of CVT-3146 (0.1-2.5 g/kg) or adenosine (10 -250 g/kg) caused a dose-dependent increase in the coronary blood flow (CBF) and a dose-dependent decrease in the late diastolic coronary resistance. Although the maximal increase in CBF response to the two drugs was not significantly different, the ED 50 of CVT-3146 and adenosine were 0.45 Ϯ 0.07 g/kg and 47 Ϯ 7.77 g/kg, respectively. The highest dose of CVT-3146 caused a much longer coronary vasodilation than the highest dose of adenosine. There were no significant differences in increases in cardiac output induced by higher doses of CVT-3146 or adenosine. Most importantly, CVT-3146 resulted in a smaller decrease in total peripheral resistance (TPR) compared to that seen with adenosine. In addition, CVT-3146 yielded a smaller increase in the lower body flow (LBF) than adenosine. Adenosine also caused dose-dependent renal vasoconstriction, whereas CVT-3146 did not affect the renal blood flow. The administration of CVT-3146 or adenosine caused a dose-dependent vasodilation in the mesentery, which was not significantly different from each other. In summary, CVT-3146 is a 100-fold more potent coronary vasodilator than adenosine. CVT-3146 causes smaller decreases in TPR and smaller increases in LBF than those induced by adenosine, indicating that it is more selective for coronary than peripheral vasodilation. Furthermore, CVT-3146 did not cause renal vasoconstriction. These features make CVT-3146 a better candidate for pharmacologic stress testing.Exercise is a common method of physiologic stress testing and is widely used in the diagnosis of coronary artery disease with radionuclide agents. However, for those who are unable to exercise adequately, an alternative procedure is needed. Pharmacologic stress testing with radionuclide agents is an option, which has been used for more than 20 years in the diagnosis of coronary artery disease. Two kinds of agents, coronary vasodilators (adenosine and dipyridamole) and ␤-adrenergic receptor agonists (dobutamine), are used in pharmacologic stress testing. These agents exert their actions through different mechanisms. Dobutamine increases contractility and heart rate by stimulating ␤-adrenergic receptors in the heart, thereby resulting in a significant increase in CBF. Adenosine increases CBF via direct vasodilation, and dipyridamole increases the circulating concentration of adenosine by blocking its reuptake and metabolism (Mahmarian and

No abstract

No abstract